331. PERMEATION OF WIN 55,212-2, A POTENT CANNABINOID RECEPTOR AGONIST, ACROSS HUMAN TRACHEO-BRONCHIAL TISSUE (EPIAIRWAY™) IN VITRO AND RAT NASAL EPITHELIUM IN VIVO.

---

Agu¹, R.U., Valiveti¹, S., Paudel¹, K.S., Klausner², M., Hayden², P.J., Stinchcomb¹, A.S. ¹University of Kentucky College of Pharmacy, Lexington, KY, ²MatTek Corporation, Ashland, MA. Journal of Pharmacy and Pharmacology, 58, 1-7, (2006).

Summary: R-(+)-WIN 55,212-2 is prone to hepatic first-pass metabolism and variable bioavailability following oral administration. The aim of this study was to predict intranasal absorption of the compound using EpiAirway™ tissue culture. Permeation experiments of R-(+)-WIN 55,212-2 mesylate formulations with 2% dimethyl-β-cyclodextrin (DMβCD), 2% randomly methylated-β-cyclodextrin (RAMβCD), 1:1 propylene glycol:saline [PG:S (1:1)] and 1.5% propylene glycol + 3% Tween 80 (PG+TW80) were conducted in vitro and in vivo using EpiAirway™ tissue and an anesthetized rat nasal absorption model, respectively. Samples were analyzed by LC-MS and rat plasma data was analyzed with WinNonlin Pharmacokinetic software. Mucosal tolerance was screened using transepithelial electrical resistance (TEER), paracellular marker permeation, and tissue viability as indices. Relative to PG+TW80 (control), PG:S (1:1), RAMβCD, and DMβCD resulted in a 24-, 20-, and 17-fold WIN 55,212-2 permeation increase in vitro, respectively. Similarly, the in vivo absolute bioavailabilities were 0.61, 0.58, 0.64 and 0.1 for PG:S (1:1), RAMβCD, DMβCD, and PG+TW80, respectively. Although TEER was significantly reduced by all the formulations in vitro, the viability of the tissue was reduced only by the DMβCD formulation. Significant improvement in absorption of R-(+)-WIN 55,212-2 mesylate was achieved using methylated cyclodextrins and propylene glycol-based cosolvent. EpiAirway™ permeation of R-(+)-WIN 55,212-2 mesylate in vitro correlated well with its in vivo nasal bioavailability in the rat. This study confirms the relevance of the EpiAirway™ tissue system as a model for screening nasal drug absorption of pharmaceutical formulations. Acknowledgments: MatTek Corporation and American Cancer Society RPG-00-027-01-CDD.

====================

Request an Electronic Copy (PDF format) of this Technical Paper

====================

EpiAirway Data Sheet

EpiAirway Specifications

EpiAirway Technical References

---

Applications: Drug delivery - intranasal, Transmucosal permeation/penetration

Keywords: Cannabidiol, Cannabinoid, Drug delivery studies, EpiAirway, HEPES buffer, Intranasal (IN), Intravenous (IV), MTT, MTT ET-50 tissue viability assay, MTT assay, Metabolism, Mucocillary clearance, Mucosal tolerance, Mucous dilution, Mucous protection, Nasal absorption, Nasal mucosa, Permeability, Permeability coefficient, Permeation, Perripheral cannabinoid receptors, Pharmacokinetic, Rat nasal epithelium, Toxicity studies, Tracheal/Bronchial epithelial cells

Endpoints: MTT assay, Sodium Fluorescein Permeation

Materials Tested: Dimethyl-beta-cyclodextrin (DM-beta-CD), Propyleneglycol (PG), Randomly methylated-beta-cyclodextrin (RAM-beta-CD), Trimethyl-beta- cyclodextrin (TM-beta-CD)

---